1. Field of the Invention
The present invention concerns nucleotide analogs and their compositions and use. In particular it relates to novel (phosphonomethoxy) methoxy purine/pyrimidine derivatives.
2. Background of the Invention
Infectious viral diseases are recognized as an important medical problem. Progress against infectious viral disease requires the development of drugs with antiviral activity while remaining benign to normal cell lines. Among the antiviral agents currently under study which seem to possess selectivity are nucleoside analogs. In general, these compounds are structural analogs of the naturally occurring nucleosides. Structural modification in either the purine or pyrimidine base nucleus and/or the saccharide component results in a synthetically modified nucleoside derivative which, when incorporated into a viral nucleic acid forming process, acts to disrupt further synthesis of viral nucleic acid.
Effectiveness of these antiviral agents depends on selective conversion by viral enzymes, but not by host enzymes, to the corresponding nucleotide analog which is then converted to the triphosphate and incorporation into viral nucleic acid occurs. A problem with this antiviral strategy has been the emergence of certain viral strains whose enzymes poorly promote phosphorylation of the nucleoside analogs. To circumvent this problem, intact nucleotide analogs appear to be potentially quite useful as antivirals for incorporation into viral nucleic acid.
A number of 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine and pyrimidine have been evaluated for their antiviral properties. Gangemi, et al., Antimicrobial Agents and Chemotherapy, Vol. 33, No. 11, pp 1864-1868 (1989). The compounds of the present invention are isosteres of PME and HPMP purine and pyrimidine analogs.
European Patent Application EP-319,228 of Harnden, published Jun. 7, 1989, discloses a purine derivatives carrying a 9-phosphonomethoxyalkyloxy substituent (Formula I) exhibiting antiviral activity ##STR1## wherein R.sub.1 is hydroxy, amino, chloro or OR.sub.7 ; R.sub.7 is C.sub.1-6 alkyl, phenyl or phenyl C.sub.1-2 alkyl either of which phenyl moieties may be substituted by one or two substituents selected from halo, C.sub.1-4 alkyl or C.sub.1-4 alkoxy; R.sub.2 is amino or, when R.sub.1 is hydroxy or amino, R.sub.2 may also be hydrogen; R.sub.3 is hydrogen, hydroxymethyl or acyloxymethyl; R.sub.4 is a group of formula CH.sub.2 P(O)(OR.sub.5 )(OR.sub.6 ) wherein R.sub.5 and R.sub.6 are independently selected from hydrogen C.sub.1-6 alkyl and optionally phenyl; or R.sub.3 and R.sub.4 together are CH.sub.2 P(O)(OR.sub.6)(OCH.sub.2) wherein R.sub.6 is as previously described. The compound of the present invention differ from the compounds of EP-319,228 by the presence of the acetal group in the compounds of the present invention.
Reist and Strum in PCT/US 84/00737, published Dec. 6, 1984, disclosed new phosphonic acid analogs of nucleoside phosphates which are useful as antivirals for incorporation into viral DNA. The structural formula for these compounds is shown below as Formula II. ##STR2## wherein B is a purine or pyrimidine base; R.sup.1 and R.sup.2 together complete a beta-pentofuranose sugar or R.sup.1 is H and R.sup.2 is H or hydroxymethyl; R.sup.3 is H or OH; X is H, OH or together with Y is carbonyl oxygen and Y can also be H; Z.sup.1 and Z.sup.2 are H or alkyl.
Similarly, synthesis and anti-herpesvirus activity of phosphate and phosphonate derivatives of 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (Formula III) was disclosed by Prisbe, et al., in J. Med. Chem., 29: 671 (1986). ##STR3##
Other phosphonate nucleotide analogs of the Formula III type wherein X.dbd.CH.sub.2 have been described by R. M. Riggs et al, Nucleosides and Nucleotides, 8(5&6, 1119-1120 (1989); D. H. R. Bouton, et al., Tetrahedron Letters, No. 37, 30: 4969-4972 1972; and H. Tanaka, et al., Tetrahedron Letters, 30: 2567-2570 (1989).
Adenine phosphonic analogs (Formula IV) and their synthesis are disclosed in the UK Patent Application of Holy, et al., GB 2,134,907A published Aug. 22, 1984 ##STR4## wherein R.sup.2 and R.sup.3 are H or together complete a ribonucleoside ring; and both R.sup.4 are alternately a hydrogen and --CH.sub.2 P(O)(OH).sub.2 group.
A preferred example of one of these compounds, known as (S)-HPMPA (Formula V) was disclosed by DeClercq, et al., in Nature, 323: 464-467 (1986) and earlier by Holy, et al, Nucleic Acids Research, Symposium Series No. 14, pp. 277-278 (1984). Phosphonate compounds which are HPMPA analogs are described in South African Patent 1987/8607. In applicant's hands, (S)-HPMPA is only slightly active in mice inoculated with herpes simples virus-2. In a 21 day protocol 30% of a group of animals treated i.p. with 50 mg/kg/day of (S)-HPMPA survived. ##STR5##
European Patent Application EP-253,412 of A. Holy, et al, published on Jan. 20, 1988, discloses a series of N-phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases (Formula VI) exhibiting antiviral activity ##STR6## in which R is a hydrogen atom or a hydroxymethyl group and B is an optinally substituted pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl, or purin-9-yl residue, whereby unsubstituted adenin-9-yl is excluded. Substituent B is preferably, inter alia, guanin-9-yl.
The addition of oxygen, while antiviral activity is retained, distinguishes the compounds of the present invention from the art. There is no teaching contained in these references, or a suggested combination thereof, which would suggest or make obvious the compounds, compositions, and uses involved in the present invention.